Organic Anion Transporter 4-Mediated Transport of Olmesartan at Basal Plasma Membrane of Human Placental Barrier

• Published in: Journal of pharmaceutical sciences 2015-09, Vol.104 (9), p.3128-3135
• Main Authors: Noguchi, Saki, Nishimura, Tomohiro, Fujibayashi, Ayasa, Maruyama, Tetsuo, Tomi, Masatoshi, Nakashima, Emi
• Format: Article
• Language: English
• Subjects: Angiotensin II Type 1 Receptor Blockers - metabolism; Biological Transport - drug effects; Biological Transport - physiology; Cell Membrane - drug effects; Cell Membrane - metabolism; Chlorides - metabolism; Dehydroepiandrosterone Sulfate - pharmacology; Estrone - analogs & derivatives; Estrone - pharmacology; Female; Humans; Imidazoles - metabolism; membrane transport; membrane transporter; organic anion transporters (OAT); Organic Anion Transporters - metabolism; pharmacokinetics; placenta; Placenta - drug effects; Placenta - metabolism; Pregnancy; Sulfobromophthalein - pharmacology; Tetrazoles - metabolism; Trophoblasts - drug effects; Trophoblasts - metabolism
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.24434

Mechanisms regulating fetal transfer of olmesartan, an angiotensin-II receptor type 1 antagonist, are important as potential determinants of life-threatening adverse fetal effects. The purpose of this study was to examine the olmesartan transport mechanism through the basal plasma membrane (BM) of human syncytiotrophoblasts forming the placental barrier. Uptake of olmesartan by human placental BM vesicles was potently inhibited by dehydroepiandrosterone sulfate (DHEAS), estrone 3-sulfate, and bromosulfophthalein, which are all typical substrates of organic anion transporter (OAT) 4 localized at the BM of syncytiotrophoblasts, and was increased in the absence of chloride. In tetracycline-inducible OAT4-expressing cells, [3H]olmesartan uptake was increased by tetracycline treatment. Olmesartan uptake via OAT4 was concentration dependent with a Km of 20μM, and was increased in the absence of chloride. [3H]Olmesartan efflux via OAT4 was also observed and was trans-stimulated by extracellular chloride and DHEAS. Thus, OAT4 mediates bidirectional transport of olmesartan and appears to regulate fetal transfer of olmesartan at the BM of syncytiotrophoblasts. Efflux transport of olmesartan via OAT4 from syncytiotrophoblasts to the fetal circulation might be facilitated in the presence of an inwardly directed physiological chloride gradient and extracellular DHEAS. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3128–3135, 2015